Safety and efficacy of burosumab in improving phosphate metabolism, bone health, and quality of life in adolescents with X-linked hypophosphatemic rickets.

BACKGROUND AND OBJECTIVE: X-linked hypophosphatemic rickets (XLH) is due to loss-of-function mutations in the phosphate-regulating endopeptidase homologue on the X chromosome (PHEX) that lead to increased fibroblast growth factor 23 (FGF23) production. FGF23 excess causes renal phosphate wasting and insufficient 1,25-dihydroxyvitamin D (1,25(OH)2D) synthesis with reduced intestinal phosphate absorption, ultimately resulting in chronic hypophosphatemia. Children with XLH show typical skeletal lesions of rickets, deformities of the lower limbs, stunted growth with disproportionate short stature, bone pain, and physical dysfunctions. Burosumab, a fully human IgG1 monoclonal antibody that binds to FGF23 to inhibit its activity, is more effective to improve the biochemical and clinical signs of XLH than conventional treatment with phosphate supplements and vitamin D active metabolites. Data on adolescents with XLH during the transition period to young adulthood are few. In this prospective case series, we aimed to assess safety and efficacy of burosumab in adolescents with XLH who discontinued long-term conventional therapy. METHODS: Five Caucasian adolescents (4 males, 1 female; mean age 15.4 ± 1.5 years) with XLH were recruited and switched from conventional treatment to burosumab (0.8-1.2 mg/kg, s. c. QW2). Burosumab was continued for 12-48 months and, once discontinued, patients were followed-up for 6-12 months. In all patients, serum calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and 1,25(OH)2D levels, and renal tubular reabsorption of phosphate (TmP/GFR) values were assessed at entry and during burosumab. Intact FGF23 plasma levels were measured at entry. Patient-reported outcomes (PROs) were assessed at entry and every 3-6 months to evaluate the impact of low extremity pain, stiffness, and difficulties performing daily activities. RESULTS: At entry, all patients showed hypophosphatemia, increased intact FGF23 levels, reduced TmP/GFR, insufficient 1,25(OH)2D levels, and in four out of five increased ALP levels. Two patients had radiological signs of rickets. During burosumab, all patients showed a significant increase in serum phosphate and 1,25(OH)2D levels, and in TmP/GFR values (P < 0.05 - P < 0.0001). Serum ALP levels significantly declined (P < 0.05) to normal values. No changes of serum calcium and PTH levels (PNS) were found during burosumab. PROs significantly improved (P < 0.02 - P < 0.0001) in all patients. Four patients discontinued burosumab when they turned 18 or 19, whereas one continued the treatment since he was still younger than 18 during the study period. Four patients who suspended burosumab showed a rapid decline in serum phosphate and 1,25(OH)2D levels and in TmP/GFR values; serum ALP levels increased, and PROs progressively worsened with a significant reduction in quality of life. These consequences were not observed in the patient who continued burosumab treatment. DISCUSSION: Our data showed that conventional treatment improved only in part the signs and symptoms of XLH. Burosumab was well tolerated and was effective in improving phosphate metabolism, bone health, and PROs. All the benefits of burosumab were lost after its discontinuation. These results suggested that continuing burosumab is required to achieve and maintain the clinical benefits of the treatment during the transition to young adulthood in patients with XLH.

Combined use of minimal screw synthesis and external articulated fixation is effective for the management of supra-intercondyloid humeral fractures in the elderly? A retrospective study.

Background: Fractures of the distal humerus are relatively rare and can be a source of disabling outcomes especially if not properly treated. Therefore, the objective of the treatment must be to obtain a stable synthesis that allows early mobilization, avoiding complications such as muscular hypotonotrophy, joint rigidity or delays in consolidation that may be due to prolonged immobilization of this joint. Although ORIF treatment of these fractures may intuitively appear to be the gold standard, there is still no consensus in the literature on which type of treatment is most suitable. Patients and method: We report in this retrospective case series analysis our experience on 31 elder patients (more than 65 years old), affected by a supra-intercondyloid humerus fracture, treated using a minimal internal fixation with cannulated screws combined with the use of an external articulated elbow fixator. This methodology is less invasive but allows a stable synthesis and an early mobilization.Clinical and radiographic examinations were performed for each patient at 1, 2, 3 and 6 months after surgery. At 6 months the residual joint excursion was evaluated and the data were collected. In addition, at 6 months, each patient underwent three different functional capacity assessment questionnaires: MAYO Elbow Performance score, The Disability of the ARM, Shoulder and Hand Score (QuickDASH) and Oxford Elbow Score. Results: The healing rate was 100% with no cases of non-union, despite the old age of our patients. The average range of motions obtained at 6 months from the surgery was 111° in flexion-extension and 157° in pronation-supination for the patient with an extra-articular fracture, 88° in flexion-extension and 153° in pronation-supination for the patients with a partial articular fracture and 85° in flexion-extension and 149° in pronation-supination for the patients with a complete articular fracture. Our results in the recovery of an arc of motion in flexion-extension are slightly less performing than the results obtained with an ORIF treatment. Indeed, according to literature the mean postoperative flexion arc in an ORIF treatment of distal humerus fractures in adults is 110°.The functional results obtained were satisfactory, with an average score at 6 months from the surgery of 95/100 (Mayo score) for the patients with an extra-articular fracture, 83.3/100 for the patients with a partial articular fracture and 79/100 for the patients with a complete articular fracture. Conclusion: The results obtained, in terms of range of motions, function, pain and healing and complications rate lead us to affirm that, in selected patients, this technique can represent a valid treatment and therefore a valid option that could be considered.

Pulp chamber features, prevalence of abscesses, disease severity, and PHEX mutation in X-linked hypophosphatemic rickets.

INTRODUCTION: Rickets, growth failure, and recurrent periapical abscesses with fistulae are main signs in patients with X-linked hypophosphatemic rickets (XLH). Prevalence of abscesses, pulp chamber features, biochemical findings, disease severity, and PHEX gene mutation were examined. MATERIALS AND METHODS: Pulp chambers size, shape, and morphology were assessed by orthopantomography in XLH patients (n = 24, age 5.8 ± 1.6 years) and in sex and age-matched healthy controls (n = 23, age 6.2 ± 1.4 years). XLH patients received conventional treatment (3.5 ± 1.9 years). Pulp chamber features were assessed in teeth of primary dentition and in the permanent left mandibular first molar and compared with those of controls. Rickets severity score was assessed at wrist, knee, and ankle. RESULTS: The mean pulp chamber area/tooth area ratio, mean pulp chamber height/pulp chamber width ratio, and prominence of pulp horns into the tooth crown in primary and secondary molars were significantly higher in patients than in controls and in patients suffered abscesses than in patients without abscesses. Sixteen patients (67%) had a history of abscesses; incisors were affected more than canines and molars. Severity of rickets and mean serum parathyroid hormone (PTH) levels were significantly higher, and mean serum 1,25-dihydroxyvitamin D [1,25(OH)2D] levels significantly lower in patients suffered abscesses than in patients without abscesses. PHEX gene mutations were not correlated with dental phenotype and disease severity. CONCLUSION: Enlarged pulp chambers with altered shape and morphology affected the majority of XLH patients predisposing to recurrent periapical abscesses with fistulae. Dental phenotype was associated with severity of rickets, high serum PTH, and low serum 1,25(OH)2D levels.